EZH2 Inhibitor Enhances the STING Agonist‒Induced Antitumor Immunity in Melanoma.

J Invest Dermatol

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China. Electronic address:

Published: April 2022

AI Article Synopsis

  • STING agonists are emerging cancer immunotherapy drugs that enhance both innate and adaptive immune responses against tumors.
  • Recent research has revealed that in melanoma, STING expression is suppressed due to epigenetic factors, specifically the H3K27me3 modification, which can be reversed by EZH2 inhibitors.
  • Combining STING agonists with EZH2 inhibitors not only increases STING expression but also improves immune responses and reduces tumor growth in preclinical melanoma models, suggesting a novel and effective treatment strategy for difficult-to-treat melanoma patients.

Article Abstract

STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. Recently, multiple clinical trials of STING agonists have been conducted in hematological malignancies and solid tumors. However, STING is commonly suppressed in melanoma through mechanisms that remain unclear. We found that STING expression was epigenetically suppressed by H3K27me3 in melanoma, and EZH2 inhibitor could induce an H3K27 shift from trimethylation to acetylation, resulting in increased expression of STING. Furthermore, a combination of STING agonist and EZH2 inhibitor upregulated major histocompatibility complex class I expression and chemokine production. Whole-transcriptome analysis showed that IFN-1‒related genes were significantly upregulated in the combination treatment group. In addition, the combination treatment synergistically reduced tumor growth and increased CD8 T-cell infiltration in a poorly immunogenic melanoma mouse model B16-F10. These results showed, to our knowledge, a previously unreported mechanism underlying the epigenetic regulation of STING expression in melanoma; a combination of STING agonists and EZH2 inhibitors can boost the antitumor immune response and would be a promising treatment option for patients with melanoma who are refractory to current immunotherapies.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2021.08.437DOI Listing

Publication Analysis

Top Keywords

ezh2 inhibitor
12
sting agonists
12
sting
9
antitumor immunity
8
sting expression
8
combination sting
8
combination treatment
8
melanoma
6
ezh2
4
inhibitor enhances
4

Similar Publications

Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells.

View Article and Find Full Text PDF

There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma.

View Article and Find Full Text PDF

Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.

Ther Adv Med Oncol

January 2025

Department of Molecular Biology of Cancer, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland.

The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. is frequently mutated and/or its expression is deregulated in various cancer types.

View Article and Find Full Text PDF

The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors.

View Article and Find Full Text PDF

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase involved in cell cycle regulation, cell differentiation, and cell death and plays a role in modulating the immune response. Although it mainly functions by catalyzing the tri-methylation of H3 histone on K27 (H3K27), to inhibit the transcription of target genes, EZH2 can directly methylate several transcription factors or form complexes with them, regulating their functions. EZH2 expression/activity is often dysregulated in cancer, contributing to carcinogenesis and immune escape, thereby representing an important target in anti-cancer therapy.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!